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Neural mechanisms of atrial arrhythmias

Abstract

The past 5 years have seen great advances in the knowledge of neural mechanisms of atrial arrhythmogenesis. Direct autonomic nerve recordings demonstrate that simultaneous sympathovagal discharges and intrinsic cardiac nerve activities are common triggers of paroxysmal atrial tachycardia and atrial fibrillation. While activity of the autonomous nervous system (ANS) is crucial in triggering paroxysmal atrial fibrillation, a high incidence of sympathovagal co-activation at baseline is associated with a high vulnerability to pacing-induced sustained atrial fibrillation, suggesting that ANS has a role in the development of persistent atrial fibrillation. Modulation of ANS activity may constitute an important therapeutic strategy for the management of atrial tachyarrhythmias. Specifically, continuous, low-level stimulation of the left cervical vagus nerve effectively suppresses atrial tachyarrhythmias by reducing the nerve activity of the stellate ganglion. Clinically, compared with pulmonary vein isolation alone, the addition of ablation of intrinsic cardiac ganglia may confer better outcomes for patients with paroxysmal atrial fibrillation. These findings suggest that further investigation of the neural mechanisms of atrial arrhythmias might lead to better management of patients with atrial arrhythmias. In this article, we review the role of the ANS in the induction and maintenance of atrial arrhythmias and the role of neural modulation as a treatment strategy for atrial arrhythmias.

Key Points

  • Simultaneous sympathovagal discharges contribute to development and maintenance of atrial arrhythmias, as they increase calcium transient, trigger spontaneous calcium release from the sarcoplasmic reticulum, and shorten atrial action potentials

  • Direct nerve recordings in ambulatory animals have shown that paroxysmal atrial tachyarrhythmias are usually preceded by simultaneous sympathetic and vagal discharges and are invariably triggered by intrinsic cardiac nerve activities

  • Studies in ambulatory dogs have shown that cardiac nerve activities are also important in sustained atrial fibrillation

  • Novel strategies, including neural ablation and neural stimulation, can reduce arrhythmogenic nerve activities, but warrant further study before they can be widely applied in clinical settings

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Figure 1: Autonomic innervation of the heart.
Figure 2: The autonomic nervous system and paroxysmal atrial tachyarrhythmias.
Figure 3: ANS and persistent atrial fibrillation.
Figure 4: LL-VNS and nerve activity of the left stellate ganglion.

References

  1. 1

    Benjamin, E. J. et al. Prevention of atrial fibrillation: report from a national heart, lung, and blood institute workshop. Circulation 119, 606–618 (2009).

    PubMed  PubMed Central  Google Scholar 

  2. 2

    Haissaguerre, M. et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N. Engl. J. Med. 339, 659–666 (1998).

    CAS  Google Scholar 

  3. 3

    Chen, S. A. et al. Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation. Circulation 100, 1879–1886 (1999).

    CAS  PubMed  Google Scholar 

  4. 4

    Tan, A. Y. et al. Autonomic innervation and segmental muscular disconnections at the human pulmonary vein-atrial junction: implications for catheter ablation of atrialpulmonary vein junction. J. Am. Coll. Cardiol. 48, 132–143 (2006).

    PubMed  Google Scholar 

  5. 5

    Chou, C. C. et al. Intracellular calcium dynamics and anisotropic reentry in isolated canine pulmonary veins and left atrium. Circulation 111, 2889–2297 (2005).

    CAS  PubMed  Google Scholar 

  6. 6

    Patterson, E., Po, S. S., Scherlag, B. J. & Lazzara, R. Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation. Heart Rhythm 2, 624–631 (2005).

    PubMed  Google Scholar 

  7. 7

    Patterson, E. et al. Sodium-calcium exchange initiated by the Ca2+ transient: an arrhythmia trigger within pulmonary veins. J. Am. Coll. Cardiol. 47, 1196–1206 (2006).

    CAS  PubMed  Google Scholar 

  8. 8

    Lu, Z. et al. Autonomic mechanism for initiation of rapid firing from atria and pulmonary veins: evidence by ablation of ganglionated plexi. Cardiovasc. Res. 84, 245–252 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Armour, J. A. Cardiac neuronal hierarchy in health and disease. Am. J. Physiol. Regul. Integr. Comp. Physiol. 287, R262–R271 (2004).

    CAS  PubMed  Google Scholar 

  10. 10

    Armour, J. A. Functional anatomy of intrathoracic neurons innervating the atria and ventricles. Heart Rhythm 7, 994–996 (2010).

    PubMed  Google Scholar 

  11. 11

    Kawashima, T. The autonomic nervous system of the human heart with special reference to its origin, course, and peripheral distribution. Anat. Embryol. (Berl.) 209, 425–438 (2005).

    Google Scholar 

  12. 12

    Chiou, C. W., Eble, J. N. & Zipes, D. P. Efferent vagal innervation of the canine atria and sinus and atrioventricular nodes--the third fat pad. Circulation 95, 2573–2584 (1997).

    CAS  PubMed  Google Scholar 

  13. 13

    Armour, J. A., Murphy, D. A., Yuan, B. X., Macdonald, S. & Hopkins, D. A. Gross and microscopic anatomy of the human intrinsic cardiac nervous system. Anat. Rec. 247, 289–298 (1997).

    CAS  PubMed  Google Scholar 

  14. 14

    Yuan, B. X., Ardell, J. L., Hopkins, D. A., Losier, A. M. & Armour, J. A. Gross and microscopic anatomy of the canine intrinsic cardiac nervous system. Anat. Rec. 239, 75–87 (1994).

    CAS  PubMed  Google Scholar 

  15. 15

    Pauza, D. H., Skripka, V. & Pauziene, N. Morphology of the intrinsic cardiac nervous system in the dog: a whole-mount study employing histochemical staining with acetylcholinesterase. Cells Tissues Organs 172, 297–320 (2002).

    PubMed  Google Scholar 

  16. 16

    Randall, W. C., Milosavljevic, M., Wurster, R. D., Geis, G. S. & Ardell, J. L. Selective vagal innervation of the heart. Ann. Clin. Lab Sci. 16, 198–208 (1986).

    CAS  PubMed  Google Scholar 

  17. 17

    Nakajima, K., Furukawa, Y., Kurogouchi, F., Tsuboi, M. & Chiba, S. Autonomic control of the location and rate of the cardiac pacemaker in the sinoatrial fat pad of parasympathetically denervated dog hearts. J. Cardiovasc. Electrophysiol. 13, 896–901 (2002).

    PubMed  Google Scholar 

  18. 18

    Hou, Y. et al. Ganglionated plexi modulate extrinsic cardiac autonomic nerve input: effects on sinus rate, atrioventricular conduction, refractoriness, and inducibility of atrial fibrillation. J. Am. Coll. Cardiol. 50, 61–68 (2007).

    Google Scholar 

  19. 19

    Scherlag, B. J., Yamanashi, W., Patel, U., Lazzara, R. & Jackman, W. M. Autonomically induced conversion of pulmonary vein focal firing into atrial fibrillation. J. Am. Coll. Cardiol. 45, 1878–1886 (2005).

    Google Scholar 

  20. 20

    Lim, P. B. et al. Intrinsic cardiac autonomic stimulation induces pulmonary vein ectopy and triggers atrial fibrillation in humans. J. Cardiovasc. Electrophysiol. 22, 638–646 (2011).

    PubMed  Google Scholar 

  21. 21

    Zhou, J. et al. Gradients of atrial refractoriness and inducibility of atrial fibrillation due to stimulation of ganglionated plexi. J. Cardiovasc. Electrophysiol. 18, 83–90 (2007).

    PubMed  PubMed Central  Google Scholar 

  22. 22

    Nakagawa, H. et al. Addition of selective ablation of autonomic ganglia to pulmonary vein antrum isolation for treatment of paroxysmal and persistent atrial fibrillation [abstract 2531]. Circulation 110 (Suppl. III), 543 (2004).

    Google Scholar 

  23. 23

    Pappone, C. et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation 109, 327–334 (2004).

    Google Scholar 

  24. 24

    Lemola, K. et al. Pulmonary vein region ablation in experimental vagal atrial fibrillation: role of pulmonary veins versus autonomic ganglia. Circulation 117, 470–477 (2008).

    Google Scholar 

  25. 25

    Ter Keurs, H. E. & Boyden, P. A. Calcium and arrhythmogenesis. Physiol. Rev. 87, 457–506 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Bers, D. M. Cardiac excitation-contraction coupling. Nature 415, 198–205 (2002).

    CAS  Google Scholar 

  27. 27

    Wijffels, M. C., Kirchhof, C. J., Dorland, R. & Allessie, M. A. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation 92, 1954–1968 (1995).

    CAS  Google Scholar 

  28. 28

    Fareh, S., Villemaire, C. & Nattel, S. Importance of refractoriness heterogeneity in the enhanced vulnerability to atrial fibrillation induction caused by tachycardia-induced atrial electrical remodeling. Circulation 98, 2202–2209 (1998).

    CAS  PubMed  Google Scholar 

  29. 29

    Burashnikov, A. & Antzelevitch, C. Reinduction of atrial fibrillation immediately after termination of the arrhythmia is mediated by late phase 3 early afterdepolarization-induced triggered activity. Circulation 107, 2355–2360 (2003).

    Google Scholar 

  30. 30

    Allessie, M. A. et al. Pathophysiology and prevention of atrial fibrillation. Circulation 103, 769–777 (2001).

    CAS  Google Scholar 

  31. 31

    Sharifov, O. F. et al. Roles of adrenergic and cholinergic stimulation in spontaneous atrial fibrillation in dogs. J. Am. Coll. Cardiol. 43, 483–490 (2004).

    CAS  Google Scholar 

  32. 32

    Perez-Lugones, A. et al. Evidence of specialized conduction cells in human pulmonary veins of patients with atrial fibrillation. J. Cardiovasc. Electrophysiol. 14, 803–809 (2003).

    PubMed  Google Scholar 

  33. 33

    Block, M. I., Said, J. W., Siegel, R. J. & Fishbein, M. C. Myocardial myoglobin following coronary artery occlusion. An immunohistochemical study. Am. J. Pathol. 111, 374–379 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Tan, A. Y. et al. Ectopic atrial arrhythmias arising from canine thoracic veins during in vivo stellate ganglia stimulation. Am. J. Physiol. Heart Circ. Physiol. 295, H691–H698 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Levin, M. D. et al. Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggers. J. Clin. Invest 119, 3420–3436 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Gherghiceanu, M. et al. Interstitial Cajal-like cells (ICLC) in myocardial sleeves of human pulmonary veins. J. Cell Mol. Med. 12, 1777–1781 (2008).

    PubMed  PubMed Central  Google Scholar 

  37. 37

    Morel, E., Meyronet, D., Thivolet-Bejuy, F. & Chevalier, P. Identification and distribution of interstitial Cajal cells in human pulmonary veins. Heart Rhythm. 5, 1063–1067 (2008).

    PubMed  Google Scholar 

  38. 38

    Langton, P., Ward, S. M., Carl, A., Norell, M. A. & Sanders, K. M. Spontaneous electrical activity of interstitial cells of Cajal isolated from canine proximal colon. Proc. Natl Acad. Sci. USA 86, 7280–7284 (1989).

    CAS  PubMed  Google Scholar 

  39. 39

    Coumel, P. et al. The atrial arrhythmia syndrome of vagal origin. Arch. Mal. Coeur Vaiss. 71, 645–656 (1978).

    CAS  PubMed  Google Scholar 

  40. 40

    Coumel, P. Autonomic influences in atrial tachyarrhythmias. J. Cardiovasc. Electrophysiol. 7, 999–1007 (1996).

    CAS  PubMed  Google Scholar 

  41. 41

    Huang, J. L., Wen, Z. C., Lee, W. L., Chang, M. S. & Chen, S. A. Changes of autonomic tone before the onset of paroxysmal atrial fibrillation. Int. J. Cardiol. 66, 275–283 (1998).

    CAS  PubMed  Google Scholar 

  42. 42

    Fioranelli, M. et al. Analysis of heart rate variability five minutes before the onset of paroxysmal atrial fibrillation. Pacing Clin. Electrophysiol. 22, 743–749 (1999).

    CAS  PubMed  Google Scholar 

  43. 43

    Tomita, T. et al. Role of autonomic tone in the initiation and termination of paroxysmal atrial fibrillation in patients without structural heart disease. J. Cardiovasc. Electrophysiol. 14, 559–564 (2003).

    PubMed  Google Scholar 

  44. 44

    Dimmer, C. et al. Variations of autonomic tone preceding onset of atrial fibrillation after coronary artery bypass grafting. Am. J. Cardiol. 82, 22–25 (1998).

    CAS  PubMed  Google Scholar 

  45. 45

    Coccagna, G., Capucci, A., Bauleo, S., Boriani, G. & Santarelli, A. Paroxysmal atrial fibrillation in sleep. Sleep 20, 396–398 (1997).

    CAS  PubMed  Google Scholar 

  46. 46

    Herweg, B., Dalal, P., Nagy, B. & Schweitzer, P. Power spectral analysis of heart period variability of preceding sinus rhythm before initiation of paroxysmal atrial fibrillation. Am. J. Cardiol. 82, 869–874 (1998).

    CAS  PubMed  Google Scholar 

  47. 47

    Zimmermann, M. & Kalusche, D. Fluctuation in autonomic tone is a major determinant of sustained atrial arrhythmias in patients with focal ectopy originating from the pulmonary veins. J. Cardiovasc. Electrophysiol. 12, 285–291 (2001).

    CAS  PubMed  Google Scholar 

  48. 48

    Bettoni, M. & Zimmermann, M. Autonomic tone variations before the onset of paroxysmal atrial fibrillation. Circulation 105, 2753–2759 (2002).

    Google Scholar 

  49. 49

    Amar, D., Zhang, H., Miodownik, S. & Kadish, A. H. Competing autonomic mechanisms precede the onset of postoperative atrial fibrillation. J. Am. Coll. Cardiol. 42, 1262–1268 (2003).

    PubMed  Google Scholar 

  50. 50

    Wen, Z. C., Chen, S. A., Tai, C. T., Huang, J. L. & Chang, M. S. Role of autonomic tone in facilitating spontaneous onset of typical atrial flutter. J. Am. Coll. Cardiol. 31, 602–607 (1998).

    CAS  PubMed  Google Scholar 

  51. 51

    de Vos, C. B. et al. Autonomic trigger patterns and anti-arrhythmic treatment of paroxysmal atrial fibrillation: data from the Euro Heart Survey. Eur. Heart J. 29, 632–639 (2008).

    PubMed  Google Scholar 

  52. 52

    Elvan, A., Wylie, K. & Zipes, D. P. Pacing-induced chronic atrial fibrillation impairs sinus node function in dogs--electrophysiological remodeling. Circulation 94, 2953–2960 (1996).

    CAS  PubMed  Google Scholar 

  53. 53

    Piccirillo, G. et al. Power spectral analysis of heart rate variability and autonomic nervous system activity measured directly in healthy dogs and dogs with tachycardia-induced heart failure. Heart Rhythm. 6, 546–552 (2009).

    PubMed  PubMed Central  Google Scholar 

  54. 54

    Gomes, J. A., Kang, P. S., Matheson, M., Gough, W. B. Jr & El Sherif, N. Coexistence of sick sinus rhythm and atrial flutter-fibrillation. Circulation 63, 80–86 (1981).

    CAS  PubMed  Google Scholar 

  55. 55

    Barrett, C. J. et al. What sets the long-term level of renal sympathetic nerve activity: a role for angiotensin II and baroreflexes? Circ. Res. 92, 1330–1336 (2003).

    CAS  PubMed  Google Scholar 

  56. 56

    Jung, B. C. et al. Circadian variations of stellate ganglion nerve activity in ambulatory dogs. Heart Rhythm 3, 78–85 (2006).

    CAS  PubMed  Google Scholar 

  57. 57

    Jayachandran, J. V. et al. Atrial fibrillation produced by prolonged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation. Circulation 101, 1185–1191 (2000).

    CAS  PubMed  Google Scholar 

  58. 58

    Chang, C. M. et al. Nerve sprouting and sympathetic hyperinnervation in a canine model of atrial fibrillation produced by prolonged right atrial pacing. Circulation 103, 22–25 (2001).

    CAS  PubMed  Google Scholar 

  59. 59

    Lu, Z. et al. Atrial fibrillation begets atrial fibrillation: autonomic mechanism for atrial electrical remodeling induced by short-term rapid atrial pacing. Circ. Arrhythm. Electrophysiol. 1, 184–192 (2008).

    PubMed  PubMed Central  Google Scholar 

  60. 60

    Tan, A. Y. et al. Neural mechanisms of paroxysmal atrial fibrillation and paroxysmal atrial tachycardia in ambulatory canines. Circulation 118, 916–925 (2008).

    PubMed  PubMed Central  Google Scholar 

  61. 61

    Ogawa, M. et al. Left stellate ganglion and vagal nerve activity and cardiac arrhythmias in ambulatory dogs with pacing-induced congestive heart failure. J. Am. Coll. Cardiol. 50, 335–343 (2007).

    PubMed  Google Scholar 

  62. 62

    Ogawa, M. et al. Cryoablation of stellate ganglia and atrial arrhythmia in ambulatory dogs with pacing-induced heart failure. Heart Rhythm 6, 1772–1779 (2009).

    PubMed  PubMed Central  Google Scholar 

  63. 63

    Choi, E.-K. et al. Intrinsic cardiac nerve activity and paroxysmal atrial tachyarrhythmia in ambulatory dogs. Circulation 121, 2615–2623 (2010).

    PubMed  PubMed Central  Google Scholar 

  64. 64

    Nishida, K. et al. The role of pulmonary veins vs. autonomic ganglia in different experimental substrates of canine atrial fibrillation. Cardiovasc. Res. 89, 825–833 (2011).

    CAS  PubMed  Google Scholar 

  65. 65

    Lin, J. et al. Autonomic mechanism to explain complex fractionated atrial electrograms (CFAE). J. Cardiovasc. Electrophysiol. 18, 1197–1205 (2007).

    PubMed  Google Scholar 

  66. 66

    Lu, Z. et al. Autonomic mechanism for complex fractionated atrial electrograms: evidence by fast fourier transform analysis. J. Cardiovasc. Electrophysiol. 19, 835–842 (2008).

    PubMed  Google Scholar 

  67. 67

    Katritsis, D., Giazitzoglou, E., Sougiannis, D., Voridis, E. & Po, S. S. Complex fractionated atrial electrograms at anatomic sites of ganglionated plexi in atrial fibrillation. Europace 11, 308–315 (2009).

    Google Scholar 

  68. 68

    Pokushalov, E. et al. Selective ganglionated plexi ablation for paroxysmal atrial fibrillation. Heart Rhythm 6, 1257–1264 (2009).

    PubMed  PubMed Central  Google Scholar 

  69. 69

    Nademanee, K. et al. A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J. Am. Coll. Cardiol. 43, 2044–2053 (2004).

    Google Scholar 

  70. 70

    Jahangir, A. et al. Long-term progression and outcomes with aging in patients with lone atrial fibrillation: a 30-year follow-up study. Circulation 115, 3050–3056 (2007).

    PubMed  PubMed Central  Google Scholar 

  71. 71

    Shen, M. J. et al. Patterns of baseline autonomic nerve activity and the development of pacing-induced sustained atrial fibrillation. Heart Rhythm 8, 583–589 (2011).

    PubMed  Google Scholar 

  72. 72

    Elvan, A., Huang, X. D., Pressler, M. L. & Zipes, D. P. Radiofrequency catheter ablation of the atria eliminates pacing-induced sustained atrial fibrillation and reduces connexin 43 in dogs. Circulation 96, 1675–1685 (1997).

    CAS  PubMed  Google Scholar 

  73. 73

    Elvan, A., Pride, H. P., Eble, J. N. & Zipes, D. P. Radiofrequency catheter ablation of the atria reduces inducibility and duration of atrial fibrillation in dogs. Circulation 91, 2235–2244 (1995).

    CAS  PubMed  Google Scholar 

  74. 74

    Bauer, A. et al. Effects of circumferential or segmental pulmonary vein ablation for paroxysmal atrial fibrillation on cardiac autonomic function. Heart Rhythm 3, 1428–1435 (2006).

    PubMed  Google Scholar 

  75. 75

    Katritsis, D. G. et al. Rapid pulmonary vein isolation combined with autonomic ganglia modification: a randomized study. Heart Rhythm 8, 672–678 (2010).

    PubMed  Google Scholar 

  76. 76

    Ohkubo, K. et al. Combined effect of pulmonary vein isolation and ablation of cardiac autonomic nerves for atrial fibrillation. Int. Heart J. 49, 661–670 (2008).

    PubMed  Google Scholar 

  77. 77

    Bagge, L. et al. Epicardial off-pump pulmonary vein isolation and vagal denervation improve long-term outcome and quality of life in patients with atrial fibrillation. J. Thorac. Cardiovasc. Surg. 137, 1265–1271 (2009).

    PubMed  Google Scholar 

  78. 78

    Scherlag, B. J. et al. Electrical stimulation to identify neural elements on the heart: their role in atrial fibrillation. J. Interv. Card. Electrophysiol. 13 (Suppl. 1), 37–42 (2005).

    PubMed  Google Scholar 

  79. 79

    Scanavacca, M. et al. Selective atrial vagal denervation guided by evoked vagal reflex to treat patients with paroxysmal atrial fibrillation. Circulation 114, 876–885 (2006).

    PubMed  PubMed Central  Google Scholar 

  80. 80

    Katritsis, D. et al. Anatomic approach for ganglionic plexi ablation in patients with paroxysmal atrial fibrillation. Am. J. Cardiol. 102, 330–334 (2008).

    Google Scholar 

  81. 81

    Lemery, R., Birnie, D., Tang, A. S., Green, M. & Gollob, M. Feasibility study of endocardial mapping of ganglionated plexuses during catheter ablation of atrial fibrillation. Heart Rhythm 3, 387–396 (2006).

    Google Scholar 

  82. 82

    Cummings, J. E. et al. Preservation of the anterior fat pad paradoxically decreases the incidence of postoperative atrial fibrillation in humans. J. Am. Coll. Cardiol. 43, 994–1000 (2004).

    PubMed  Google Scholar 

  83. 83

    Hirose, M., Leatmanoratn, Z., Laurita, K. R. & Carlson, M. D. Partial vagal denervation increases vulnerability to vagally induced atrial fibrillation. J. Cardiovasc. Electrophysiol. 13, 1272–1279 (2002).

    PubMed  Google Scholar 

  84. 84

    Kangavari, S. et al. Radiofrequency catheter ablation and nerve growth factor concentration in humans. Heart Rhythm 3, 1150–1155 (2006).

    PubMed  Google Scholar 

  85. 85

    Okuyama, Y. et al. Sympathetic nerve sprouting induced by radiofrequency catheter ablation in dogs. Heart Rhythm 1, 712–717 (2005).

    Google Scholar 

  86. 86

    Sakamoto, S. et al. Vagal denervation and reinnervation after ablation of ganglionated plexi. J. Thorac. Cardiovasc. Surg. 139, 444–452 (2010).

    PubMed  Google Scholar 

  87. 87

    Po, S. S., Nakagawa, H. & Jackman, W. M. Localization of left atrial ganglionated plexi in patients with atrial fibrillation. J. Cardiovasc. Electrophysiol. 20, 1186–1189 (2009).

    PubMed  PubMed Central  Google Scholar 

  88. 88

    Oh, S., Choi, E. K. & Choi, Y. S. Short-term autonomic denervation of the atria using botulinum toxin. Korean Circ. J. 40, 387–390 (2010).

    PubMed  PubMed Central  Google Scholar 

  89. 89

    Stavrakis, S. et al. Suppression of atrial fibrillation inducibility by vasostatin-1. Heart Rhythm 8, S265 (2011).

    Google Scholar 

  90. 90

    Yu, L. et al. Autonomic denervation with magnetic nanoparticles. Circulation 122, 2653–2659 (2010).

    CAS  PubMed  Google Scholar 

  91. 91

    Moss, A. J. & McDonald, J. Unilateral cervicothoracic sympathetic ganglionectomy for the treatment of long QT interval syndrome. N. Engl. J. Med. 285, 903–904 (1971).

    CAS  PubMed  Google Scholar 

  92. 92

    Schwartz, P. J. et al. Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome. Circulation 109, 1826–1833 (2004).

    PubMed  Google Scholar 

  93. 93

    Carpenter, R. J. et al. The acute effects of acupuncture upon autonomic balance in healthy subjects. Am. J. Chin. Med. 38, 839–847 (2010).

    PubMed  Google Scholar 

  94. 94

    Abad-Alegria, F., Pomaron, C., Aznar, C., Munoz, C. & Adelantado, S. Objective assessment of the sympatholytic action of the Nei-Kuan acupoint. Am. J. Chin. Med. 29, 201–210 (2001).

    CAS  PubMed  Google Scholar 

  95. 95

    Huang, S. T. et al. Increase in the vagal modulation by acupuncture at neiguan point in the healthy subjects. Am. J. Chin. Med. 33, 157–164 (2005).

    PubMed  Google Scholar 

  96. 96

    Li, P., Pitsillides, K. F., Rendig, S. V., Pan, H. L. & Longhurst, J. C. Reversal of reflex-induced myocardial ischemia by median nerve stimulation: a feline model of electroacupuncture. Circulation 97, 1186–1194 (1998).

    CAS  PubMed  Google Scholar 

  97. 97

    Nishijo, K., Mori, H., Yosikawa, K. & Yazawa, K. Decreased heart rate by acupuncture stimulation in humans via facilitation of cardiac vagal activity and suppression of cardiac sympathetic nerve. Neurosci. Lett. 227, 165–168 (1997).

    CAS  PubMed  Google Scholar 

  98. 98

    Lomuscio, A., Belletti, S., Battezzati, P. M. & Lombardi, F. Efficacy of acupuncture in preventing atrial fibrillation recurrences after electrical cardioversion. J. Cardiovasc. Electrophysiol. 22, 241–247 (2011).

    PubMed  Google Scholar 

  99. 99

    Chai, C. Y., Huang, T. F. & Wang, S. C. Mechanisms of cardiac arrhythmias induced by baroceptor reflexes in cats. Am. J. Physiol. 215, 1316–1323 (1968).

    CAS  PubMed  Google Scholar 

  100. 100

    Zhou, X., Vance, F. L. 4th, Sims, A. L., Sreenan, C. M. & Ideker, R. E. Prevention of high incidence of neurally mediated ventricular arrhythmias by afferent nerve stimulation in dogs. Circulation 101, 819–824 (2000).

    CAS  PubMed  Google Scholar 

  101. 101

    Zhou, X., Wolf, P. D., Smith, W. M., Blanchard, S. M. & Ideker, R. E. Effects of peroneal nerve stimulation on hypothalamic stimulation-induced ventricular arrhythmias in rabbits. Am. J. Physiol. 267, H2032–H2041 (1994).

    CAS  PubMed  Google Scholar 

  102. 102

    Vanoli, E. et al. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ. Res. 68, 1471–1481 (1991).

    CAS  PubMed  Google Scholar 

  103. 103

    Li, S. et al. Low-level vagosympathetic stimulation: a paradox and potential new modality for the treatment of focal atrial fibrillation. Circ. Arrhythm. Electrophysiol. 2, 645–651 (2009).

    PubMed  Google Scholar 

  104. 104

    Yu, L. et al. Low-level vagosympathetic nerve stimulation inhibits atrial fibrillation inducibility: direct evidence by neural recordings from intrinsic cardiac ganglia. J. Cardiovasc. Electrophysiol. 22, 455–463 (2010).

    PubMed  Google Scholar 

  105. 105

    Sheng, X. et al. Prevention and reversal of atrial fibrillation inducibility and autonomic remodeling by low-level vagosympathetic nerve stimulation. J. Am. Coll. Cardiol. 57, 563–571 (2011).

    PubMed  Google Scholar 

  106. 106

    Shen, M. J. et al. Continuous low-level vagus nerve stimulation reduces stellate ganglion nerve activity and paroxysmal atrial tachyarrhythmias in ambulatory canines. Circulation 123, 2204–2212 (2011).

    PubMed  PubMed Central  Google Scholar 

  107. 107

    Viskin, S. et al. Circadian variation of symptomatic paroxysmal atrial fibrillation. Data from almost 10,000 episodes. Eur. Heart J. 20, 1429–1434 (1999).

    CAS  PubMed  Google Scholar 

  108. 108

    Muller, J. E. et al. Circadian variation in the frequency of sudden cardiac death. Circulation 75, 131–138 (1987).

    CAS  PubMed  Google Scholar 

  109. 109

    Dietrich, S. et al. A novel transcutaneous vagus nerve stimulation leads to brainstem and cerebral activations measured by functional MRI [German]. Biomed. Tech. (Berl.) 53, 104–111 (2008).

    Google Scholar 

  110. 110

    Yu, L. et al. Low level transcutaneous electrical stimulation supresses atrial fibrillation inducibility. Heart Rhythm 8, S262 (2011).

    Google Scholar 

  111. 111

    Ardell, J. L. The cardiac neuronal hierarchy and susceptibility to arrhythmias. Heart Rhythm 8, 590–591 (2010).

    PubMed  PubMed Central  Google Scholar 

  112. 112

    Ardell, J. L., Cardinal, R., Vermeulen, M. & Armour, J. A. Dorsal spinal cord stimulation obtunds the capacity of intrathoracic extracardiac neurons to transduce myocardial ischemia. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297, R470–R477 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Southerland, E. M. et al. Preemptive, but not reactive, spinal cord stimulation mitigates transient ischemia-induced myocardial infarction via cardiac adrenergic neurons. Am. J. Physiol. Heart Circ. Physiol. 292, H311–H317 (2007).

    CAS  PubMed  Google Scholar 

  114. 114

    Qin, C. et al. Modulation of neuronal activity in dorsal column nuclei by upper cervical spinal cord stimulation in rats. Neuroscience 164, 770–776 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Wu, M., Linderoth, B. & Foreman, R. D. Putative mechanisms behind effects of spinal cord stimulation on vascular diseases: a review of experimental studies. Auton. Neurosci. 138, 9–23 (2008).

    PubMed  PubMed Central  Google Scholar 

  116. 116

    Olgin, J. E. et al. Effects of thoracic spinal cord stimulation on cardiac autonomic regulation of the sinus and atrioventricular nodes. J. Cardiovasc. Electrophysiol. 13, 475–481 (2002).

    PubMed  Google Scholar 

  117. 117

    Lopshire, J. C. et al. Spinal cord stimulation improves ventricular function and reduces ventricular arrhythmias in a canine postinfarction heart failure model. Circulation 120, 286–294 (2009).

    PubMed  Google Scholar 

  118. 118

    Lanza, G. A. et al. Spinal cord stimulation for the treatment of refractory angina pectoris: a multicenter randomized single-blind study (the SCS-ITA trial). Pain 152, 45–52 (2011).

    PubMed  Google Scholar 

  119. 119

    Andrell, P. et al. Long-term effects of spinal cord stimulation on angina symptoms and quality of life in patients with refractory angina pectoris--results from the European Angina Registry Link Study (EARL). Heart 96, 1132–1136 (2010).

    CAS  PubMed  Google Scholar 

  120. 120

    US National Library of Medicine. ClinicalTrials.gov [online], (2011).

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Acknowledgements

This study was supported in part by NIH Grants P01HL78931, R01HL78932, R01HL71140, R21HL106554, a Heart Rhythm Society Fellowship in Cardiac Pacing and Electrophysiology (M. J. Shen) and a Medtronic-Zipes Endowment (P.-S. Chen).

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All authors researched data and wrote the article, contributed substantially to the discussion of content, and reviewed and edited the manuscript before submission.

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Correspondence to Peng-Sheng Chen.

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Shen, M., Choi, EK., Tan, A. et al. Neural mechanisms of atrial arrhythmias. Nat Rev Cardiol 9, 30–39 (2012). https://doi.org/10.1038/nrcardio.2011.139

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